Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.31 (AMP-activated protein kinase)
 13,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AMP-activated protein kinase (AMPK), a heterotrimeric serine/threonine kinase, is activated by conditions leading to an increase of the intracellular AMP:ATP ratio. However, how AMPK is regulated under the oxidative stress is completely unknown. In the present study, we examined effects of the oxidative agent H(2)O(2) on AMPK. AMPK was transiently and concentration-dependently activated by H(2)O(2) in NIH-3T3 cells. This activation was tightly associated with an increased AMP:ATP ratio, an electrophoretic mobility shift of AMPK alpha1 catalytic subunit, and an increased phosphorylation level of AMPK alpha1 threonine 172, which is a major in vitro phosphorylation site by the upstream AMPK kinase. All of these events were significantly blocked by the pretreatment of 0.5% dimethyl sulfoxide, a potent hydroxyl radical scavenger, indicating that AMPK cascades are highly sensitive to the oxidative stress. Interestingly, a specific tyrosine kinase inhibitor, genistein, further stimulated the H(2)O(2)-induced AMPK activity by 70% without altering the AMP:ATP. Taken together, our results suggest that AMP:ATP ratio is the major parameter to which AMPK responds under the oxidative stress, but AMPK may be regulated in part by a tyrosine kinase-dependent pathway, which is independent of the cellular adenosine nucleotides level.
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PMID:The regulation of AMP-activated protein kinase by H(2)O(2). 1154 58

AMP-activated protein kinase (AMPK) is a highly conserved sensor of cellular energy status found in all eukaryotic cells. AMPK is activated by stimuli that increase the cellular AMP/ATP ratio. Essential to activation of AMPK is its phosphorylation at Thr-172 by an upstream kinase, AMPKK, whose identity in mammalian cells has remained elusive. Here we present biochemical and genetic evidence indicating that the LKB1 serine/threonine kinase, the gene inactivated in the Peutz-Jeghers familial cancer syndrome, is the dominant regulator of AMPK activation in several mammalian cell types. We show that LKB1 directly phosphorylates Thr-172 of AMPKalpha in vitro and activates its kinase activity. LKB1-deficient murine embryonic fibroblasts show nearly complete loss of Thr-172 phosphorylation and downstream AMPK signaling in response to a variety of stimuli that activate AMPK. Reintroduction of WT, but not kinase-dead, LKB1 into these cells restores AMPK activity. Furthermore, we show that LKB1 plays a biologically significant role in this pathway, because LKB1-deficient cells are hypersensitive to apoptosis induced by energy stress. On the basis of these results, we propose a model to explain the apparent paradox that LKB1 is a tumor suppressor, yet cells lacking LKB1 are resistant to cell transformation by conventional oncogenes and are sensitive to killing in response to agents that elevate AMP. The role of LKB1/AMPK in the survival of a subset of genetically defined tumor cells may provide opportunities for cancer therapeutics.
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PMID:The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. 2462 16

Obesity is an epidemic in Western society, and causes rapidly accelerating rates of type 2 diabetes and cardiovascular disease. The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a 'fuel gauge' to monitor cellular energy status. We investigated the potential role of AMPK in the hypothalamus in the regulation of food intake. Here we report that AMPK activity is inhibited in arcuate and paraventricular hypothalamus (PVH) by the anorexigenic hormone leptin, and in multiple hypothalamic regions by insulin, high glucose and refeeding. A melanocortin receptor agonist, a potent anorexigen, decreases AMPK activity in PVH, whereas agouti-related protein, an orexigen, increases AMPK activity. Melanocortin receptor signalling is required for leptin and refeeding effects on AMPK in PVH. Dominant negative AMPK expression in the hypothalamus is sufficient to reduce food intake and body weight, whereas constitutively active AMPK increases both. Alterations of hypothalamic AMPK activity augment changes in arcuate neuropeptide expression induced by fasting and feeding. Furthermore, inhibition of hypothalamic AMPK is necessary for leptin's effects on food intake and body weight, as constitutively active AMPK blocks these effects. Thus, hypothalamic AMPK plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signals and in energy balance.
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PMID:AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. 1505 5

The cloning of salt-inducible kinase-1 (SIK1) that was specifically expressed in the adrenal glands of high-salt diet-fed rats led to subsequent cloning of adipose-specific SIK2 and rather ubiquitous SIK3. The three enzymes constitute a novel serine/threonine kinase subfamily, a member of AMP-activated protein kinase (PKA) family. Physiological roles of SIK1 and SIK2 have been investigated. The SIK1 transcript was expressed very early in the ACTH-stimulated Y1 cells, even before the expression of transcripts for CYP11A and StAR protein. Forced expression of SIK1 inhibited the ACTH-dependent expression of CYP11A- and StAR protein-genes. Cotransfection assays employing CRE-reporter gene showed that SIK1 could repress the PKA-dependent activation of CRE by acting on the bZIP domain of the CRE-binding protein (CREB), though the target site of SIK1-mediated phosphorylation has yet to be determined. ACTH/PKA-dependent nucleocytoplasmic shuttling of SIK1 took place in Y1 cells, implying that the intracellular movement of SIK1 might be a physiologically important determining factor for regulation of steroidogenic gene expression in the early phase of ACTH-stimulation. The SIK2 gene was expressed in 3T3-L1 cells at a very early stage of adipogenesis. SIK2 could phosphorylate Ser-794 of human insulin-receptor-substrate-1 (IRS-1) in vitro as well as in vivo. In addition, the SIK2 activity in db/db mice adipose tissues was significantly higher than that in wild-type adipose. These results strongly suggest that SIK2 may play important role(s) in modulating the insulin-signaling cascade of adipocytes, and thus, may be involved in the development of insulin resistance. Taken together, these results suggest that the SIK isoforms regulate hormonal signal transduction in both adrenal and adipose tissues.
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PMID:Salt-inducible kinase (SIK) isoforms: their involvement in steroidogenesis and adipogenesis. 1513 8

The serine/threonine kinase Akt is an upstream positive regulator of the mammalian target of rapamycin (mTOR). However, the mechanism by which Akt activates mTOR is not fully understood. The known pathway by which Akt activates mTOR is via direct phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which is a negative regulator of mTOR. Here we establish an additional pathway by which Akt inhibits TSC2 and activates mTOR. We provide for the first time genetic evidence that Akt regulates intracellular ATP level and demonstrate that Akt is a negative regulator of the AMP-activated protein kinase (AMPK), which is an activator of TSC2. We show that in Akt1/Akt2 DKO cells AMP/ATP ratio is markedly elevated with concomitant increase in AMPK activity, whereas in cells expressing activated Akt there is a dramatic decrease in AMP/ATP ratio and a decline in AMPK activity. Currently, the Akt-mediated phosphorylation of TSC2 and the inhibition of AMPK-mediated phosphorylation of TSC2 are viewed as two separate pathways, which activate mTOR. Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of TSC2 and activation of mTOR both through direct phosphorylation and by inhibition of AMPK-mediated phosphorylation of TSC2. We propose that the activation of mTOR by Akt-mediated cellular energy and inhibition of AMPK is the predominant pathway by which Akt activates mTOR in vivo.
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PMID:Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. 1602 21

The exposure of homeothermic animals to a cold environment leads to a powerful activation of orexigenic signalling which is accompanied by molecular and functional resistance to insulin-induced inhibition of feeding. Recent evidence suggests that AMPK participates in nutrient-dependent control of satiety and adiposity. The objective of the present study was to evaluate the effect of cold exposure upon the molecular activation of AMPK signalling in the hypothalamus of rats. Immunoblotting demonstrated that cold exposure per se is sufficient for inducing, on a time-dependent basis, the molecular activation of the serine/threonine kinase AMP-activated protein kinase (AMPK) and inactivation of the acetyl-CoA carboxylase (ACC). These molecular phenomena were accompanied by resistance to nutrient-induced inactivation of AMPK and activation of ACC. Moreover, cold-exposure led to a partial inhibition of a feeding-induced anorexigenic response, which was paralleled by resistance to insulin-induced suppression of feeding. Finally, cold exposure significantly impaired insulin-induced inhibition of AMPK through a mechanism dependent on the molecular cross-talk between phosphatidylinositol-3(PI3)-kinase/Akt and AMPK. In conclusion, increased feeding during cold exposure results, at least in part, from resistance to insulin- and nutrient-dependent anorexigenic signalling in the hypothalamus.
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PMID:Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals. 1614 Dec 67

The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a cellular fuel gauge that regulates metabolic pathways in glucose and fatty acid metabolism and protein synthesis. Recent data strongly implicate the AMPK-acetyl CoA carboxylase (ACC)-malonyl CoA pathway in the hypothalamus in the regulation of food intake, body weight and hepatic glucose production. Furthermore, data indicate that AMPK is a mediator of the effects of adipocyte-derived and gut-derived hormones and peptides on fatty acid oxidation and glucose uptake in peripheral tissues. Studies are now elucidating the potential role of kinases upstream of AMPK in these metabolic effects. In addition, recently, several novel downstream effectors of AMPK have been identified. The AMPK pathway in the hypothalamus and peripheral tissues coordinately integrates inputs from multiple hormones, peptides and nutrients to maintain energy homeostasis.
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PMID:AMPK integrates nutrient and hormonal signals to regulate food intake and energy balance through effects in the hypothalamus and peripheral tissues. 1670 29

LKB1 is a 50 kDa serine/threonine kinase that phosphorylates and activates the catalytic subunit of AMPK at its T-loop residue Thr 172. We prepared adenoviruses expressing the constitutive active (wild-type) form (CA) or dominant negative (kinase inactive, D194A mutant) form (DN) of LKB1 and overexpressed these proteins in cultured myotubes (C2C12 cells) and rat hepatoma cells (FAO cells). When analyzed by immunoblotting with the antibody against Thr172-phosphorylated AMPK, the phosphorylation of AMPK was increased (2.5-fold) and decreased (0.4-fold) in cells expressing CA and DN LKB1, respectively, as compared with Lac-Z expressing control cells. Immunoprecipitation experiments, using isoform-specific antibody, revealed these alterations of AMPK phosphorylation to be attributable to altered phosphorylation of AMPK alpha2, but not alpha1 catalytic subunits, strongly suggesting the alpha2 catalytic subunit to be the major substrate for LKB1 in mammalian cells. In addition, adiponectin or AICAR-stimulated AMPK phosphorylation was inhibited by overexpression of DN LKB1, while phenformin-stimulated phosphorylation was unaffected. These results may explain the difference in AMPK activation mechanisms between AMP and phenformin, and also indicate that AMPK phosphorylation by LKB1 is involved in AMP-stimulated AMPK activation. As a downstream target for AMPK, AICAR-induced glucose uptake and ACCbeta phosphorylation were found to be significantly reduced in DN LKB1 expressing C2C12 cells. The expression of key enzymes for gluconeogenesis, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was also dependent on LKB1 activities in FAO cells. These results demonstrate that LKB1 is a crucial regulator of AMPK activation in muscle and liver cells and, therefore, that LKB1 activity is potentially of importance to our understanding of glucose and lipid metabolism.
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PMID:LKB1, an upstream AMPK kinase, regulates glucose and lipid metabolism in cultured liver and muscle cells. 1708 19

Resveratrol has been reported to possess therapeutic effects for various cancers including colon cancers. In this article, the molecular basis of resveratrol with emphasis on its ability to control intracellular signaling cascades of adenosine monophosphate (AMP)-activated protein kinase (AMPK) responsible for inducing apoptosis in drug-resistant cancer cells was investigated. Recently, the evolutionarily conserved serine/threonine kinase, AMPK, emerges as a possible target molecule of cancer control. We have investigated the effects of resveratrol on apoptosis in relation to AMPK in HT-29 cells shown chemoresistant to a cancer chemotherapeutic drug, etoposide. Resveratrol exhibited a variety of molecular events in etoposide-based combination therapy in HT-29 colon cancer cells including the AMPK activation, inhibition of cell growth, induction of apoptosis, and reactive oxygen species (ROS) generation. The involvement of AMPK signaling cascade in resveratrol-based cancer therapy was clearly shown by comparing the conditions of AMPK activated states and inactivated states. We have identified ROS as an upstream regulator of AMPK. Further investigation warrants to elucidate the mechanism by which resveratrol generates ROS and AMPK activation.
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PMID:Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway. 1740 56

AMP-activated protein kinase (AMPK, also known as SNF1A) has been primarily studied as a metabolic regulator that is activated in response to energy deprivation. Although there is relatively ample information on the biochemical characteristics of AMPK, not enough data exist on the in vivo function of the kinase. Here, using the Drosophila model system, we generated the first animal model with no AMPK activity and discovered physiological functions of the kinase. Surprisingly, AMPK-null mutants were lethal with severe abnormalities in cell polarity and mitosis, similar to those of lkb1-null mutants. Constitutive activation of AMPK restored many of the phenotypes of lkb1-null mutants, suggesting that AMPK mediates the polarity- and mitosis-controlling functions of the LKB1 serine/threonine kinase. Interestingly, the regulatory site of non-muscle myosin regulatory light chain (MRLC; also known as MLC2) was directly phosphorylated by AMPK. Moreover, the phosphomimetic mutant of MRLC rescued the AMPK-null defects in cell polarity and mitosis, suggesting MRLC is a critical downstream target of AMPK. Furthermore, the activation of AMPK by energy deprivation was sufficient to cause dramatic changes in cell shape, inducing complete polarization and brush border formation in the human LS174T cell line, through the phosphorylation of MRLC. Taken together, our results demonstrate that AMPK has highly conserved roles across metazoan species not only in the control of metabolism, but also in the regulation of cellular structures.
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PMID:Energy-dependent regulation of cell structure by AMP-activated protein kinase. 1748 97


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